Project Summary We seek to elucidate the biomechanical mechanisms that control the activation of transforming growth factor beta (TGF?), a major mediator in the progression of thoracic aortic aneurysms (TAA). In this PPG application we have put forward the provocative proposal that cells use the latent form of TGF?, which resides in the extracellular matrix (ECM), as a sensor of biomechanical changes. Upon alteration in the surrounding matrix due to inherent structural mutations or changes in surrounding forces, such as blood pressure, TGF? is mobilized to remodel the EMC. We posit that to understand the mechanisms controlling latent TGF? mobilization, we must identify the specific individual components of the latent TGF? complex. We will focus on the properties of TGF? in the development of two complementary types of vascular lesions; one involves mutant mice that have Marfan syndrome (MFS) and die from TAA. The other model employs normal mice whose aortas have been ligated to increase pressure (coarctation model) that results in rapid vascular remodeling, which we propose duplicates the early events in pressure-related promotion of TAA. Therefore, one model represents a genetic defect of the matrix with altered ECM composition, whereas the second model represents a normal matrix remodeled because of an induced stress. We will in Aim 1 identify the isoform of TGF? involved in ECM remodeling and TAA biogenesis in MFS mice (with Projects 1 and Cores B and C). In Aim 2, we will characterize the species of LTBP involved in MFS and hypertensive mice, matrix remodeling, and aneurysm formation (with Project 4) and elucidate whether the LTBP acts via TGF? or by an additional structural function (with Projects 1 and 4 and Cores B and C). In Aim 3, we will discern whether the ECM of the MFS cells and animals releases active TGF? more readily that does normal ECM when placed under mechanical stress (with Project 3 and Core C) and if changes in the ECM that block TAA formation also affect TGF? release (with Projects 1 and 4 and Core C). The information obtained from these experiments will provide an understanding of how latent TGF? contributes to TAA and thereby illustrate potential points for the development of drug therapy. !